1. Technical Field
The present invention is related to the cloning, isolation and partial characterization of a hitherto unidentified human gene. More particularly, the present invention is related to the preparation and identification of a v-erbB related human gene that is a new member of the tyrosine kinase encoding family of genes and is amplified in a human mammary carcinoma.
2. State of the Art
A number of genes have been identified as retroviral oncogenes that are responsible for inducing tumors in vivo and transforming cells in vitro (Land et al., Science 222:771-778, 1983). Some of them apparently encode transforming proteins that share a kinase domain homologous to that of pp60src, a tyrosine-specific protein kinase. The cellular cognate, encoded by the c-src gene, also exhibits tyrosine-specific kinase activity. Of particular interest is the fact that tyrosine-specific kinases are also encoded by other genes for several receptors for polypeptide growth factors, including the receptors for epidermal growth factor (EGF) (Cohen et al., J. Biol. Chem. 255:4834-4842, 1980), platelet-derived growth factor (PDGF) (Nishimura et al., Proc. Natl. Acad. Sci. USA 79:4303-4307, 1982), insulin (Kasuga et al., Nature 298:667-669, 1982), and insulin-like growth factor I (Rubin et al., Nature 305:438-440, 1983). This implies a possible link between the action of the growth factor-receptor complex and the oncogene products with tyrosine-specific kinase activity.
Recent analysis of the v-erbB gene and the EGF receptor gene indicates that the v-erbB gene is a part of the EGF receptor gene and codes for the internal domain and transmembrane portion of the receptor (Yamamoto et al., Cell 35:71-78, 1983; Downward et al., Nature 307:521-527, 1984; Ullrich et al., Nature 309:418-425, 1984). These findings, together with the extensive identity of the amino acid sequences of the v-sis protein and platelet-derived growth factor (Waterfield et al., Nature 304:35-39, 1983; Doolittle et al., Science 221:275-277, 1983), suggest that some viral oncogene products mimic the action of the polypeptide growth factor-receptor complex in activating a cellular pathway involved in cell proliferation and tumor formation.
Genetic alterations affecting proto-oncogenes of the tyrosine kinase family may play a role in spontaneous tumor development. A specific translocation affecting the c-abl locus, for example, is associated with chronic myelogenous leukemia (de Klein et al., Nature 300:765, 1982; Collins et al., Proc. Natl. Acad. Sci. USA 80:4813, 1983). Several recent studies have also documented amplification or rearrangement of the gene for the EGF receptor in certain human tumors (Libermann et al., Nature 313:144, 1985), or tumor cell lines (Ullrich et al., Nature 309:418, 1984; Lin et al., Science 224:843, 1984). However, a gene that is a new member of the tyrosine kinase family and is amplified in a human mammary carcinoma and is closely related to, but distinct from the EGF receptor gene, has not heretofore been known.